Novel mechanism of taxane resistance

July 16, 2006

Research Associate Chih-Jian Lih and others working in the laboratory of Dr. Stanley N. Cohen at Stanford University have pinpointed a gene that affects human cancer cells' sensitivity to chemotherapy - an important finding in the effort to increase the effectiveness of chemotherapy.

Their paper will be published online in advance of its scheduled August 1 publication date (www.genesdev.org).

Using an approach that randomly alters expression of mammalian cell genes, together with a screen that detects altered gene function, Dr. Cohen and colleagues identified a previously uncharacterized gene, called txr1, whose increased expression in prostate cancer cells confers resistance to taxane drugs. Taxanes are a class of widely-used chemotherapeutics (marketed as docetaxel and paclitaxel) that prevent cancer cell growth by inhibiting microtubule breakdown and subsequent cell division.

The researchers determined that txr1 promotes taxane resistance by suppressing the known anti-angiogenic and pro-apoptotic factor, thrombospondin 1 (TSP-1). This action is entirely different from mechanisms found earlier to be involved in resistance to taxanes.

Furthermore, they discovered that depletion of txr1, or treatment with TSP-1 (or a TSP-1 mimetic) restores taxane sensitivity. As acquired drug resistance poses a major limitation to the long-term efficacy of taxanes, the discovery of txr1 as a component of a novel pathway of taxane cytotoxicity opens up a new avenue to modulate chemotherapeutic drug response and sensitize cancer cells to drug treatment.
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Cold Spring Harbor Laboratory

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